International experience with secundum atrial septal defect occlusion by the buttoned device

Several devices are available for transcatheter occlusion of atrial septal defect. This report describes the international experience with the buttoned device. During a 4.5-year period ending in February 1993, 180 transcatheter atrial septal defect occlusions were performed with the buttoned device. Patient age varied between 0.6 and 76 years and stretched atrial defect diameter between 5 and 25 mm. The defects were closed with 25 to 50 mm devices delivered through 8F (148 patients) or 9F (32 patients) sheaths. Twelve patients were adults whose defects were closed to prevent recurrence of cerebrovascular accidents caused by presumed paradoxic embolism. In the remaining patients the atrial defect was closed to treat the left-to-right shunt. The atrial septal defects were effectively occluded as demonstrated by (1) decrease in pulmonary-to-systemic flow ratio from 2.1 +/- 0.6 (mean +/- SD) to 1.05 +/- 0.1 (p 2 and disappearance of the diastolic murmur by auscultation; and (3) improvement in right ventricular volume overloading by echocardiogram. However, trivial to small shunts could be detected by color Doppler studies in 76 (45%) of 168 patients in whom such data are available. Complications included unbuttoning in 13 and whole-device embolization in 1. All patients remained stable, and retrieval of the device and surgical closure of the atrial septal defect were accomplished in 10 patients. Transcatheter retrieval was used in the remaining 4 patients. The incidence of unbuttoning, a major complication of the procedure, appeared to decrease with the increasing experience of the investigators and with device modification (third-generation). The follow-up duration varied between 1 month and 4 years. Six patients required surgery during the follow-up period. In the remaining patients (n = 160), clinical examination did not reveal signs of atrial shunts. Color Doppler studies revealed either complete disappearance of the previously demonstrated shunts or further diminution of their size. The results indicate that transcatheter occlusion of the atrial septal defects with buttoned devices is feasible, relatively safe, and effective, and it appears to be a viable alternative to surgery for some patients with secundum atrial septal defect. Complications are infrequent and should improve with experience.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31234/1/0000139.pd

Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine–sulfonamide hybrids as selective BRAFV600E inhibitors

The “RAS-RAF-MEK-ERK” pathway is an important signaling pathway in melanoma. BRAFV600E(70–90%) is the most common mutation in this pathway. BRAF inhibitors have four types of conformers: type I (aC-IN/DFG-IN), type II (aC-IN/DFG-OUT), type I1/2(aC-OUT/DFG-IN), and type I/II (aC-OUT/DFG-OUT). First-and second-generation BRAF inhibitors show resistance to BRAFV600Eand are ineffective against malignancies induced by dimer BRAF mutants causing ‘paradoxical’ activation. In the present study, we performed molecular modeling of pyrimidine–sulfonamide hybrids inhibitors using 3D-QSAR, molecular docking, and molecular dynamics simulations. Previous reports reveal the importance of pyrimidine and sulfonamide moieties in the development of BRAFV600Einhibitors. Analysis of 3D-QSAR models provided novel pyrimidine sulfonamide hybrid BRAFV600Einhibitors. The designed compounds share similarities with several structural moieties present in first- and second-generation BRAF inhibitors. A total library of88 designed compounds was generated and molecular docking studies were performed with them. Four molecules (T109, T183, T160, and T126) were identified as hits and selected for detailed studies. Molecular dynamics simulations were performed at 900 ns and binding was calculated. Based on molecular docking and simulation studies, it was found that the designed compounds have better interactions with the core active site [the nucleotide (ADP or ATP) binding site, DFG motif, and the phospho-acceptor site (activation segment) of BRAFV600Eprotein than previous inhibitors. Similar to the FDA-approved BRAFV600Einhibitors the developed compounds have [aC-OUT/DFG-IN] conformation. Compounds T126, T160 and T183 interacted with DIF (Leu505), making them potentially useful againstBRAFV600Eresistance and malignancies induced by dimer BRAF mutants. The synthesis and biological evaluation of the designed molecules is in progress, which may lead to some potent BRAFV600Eselectiveinhibitors